Vasopressin, a neurohypophyseal nonapeptide which affects blood pressure and renal function, has been linked with areas in the brain implicated in cognitive function. Intranasal administration of vasopressin and a synthetic analog [1-desamino-8-D-arginine vasopressin (DDAVP)] has been reported to cause increases in learning and memory in young unimpaired human subjects when compared with placebo treatment. Three of four depressed patients demonstrated cognitive enhancement independent of changes in mood. Positive effects on recall of learned information have been reported in two patients given bilateral electroconvulsive shock therapy (ECT) while under the influence of desmopressin (DDAVP). Vasopressin and its analogs usually have been inactive by the oral route. The structures of arginine.sup.8 -vasopressin (AVP), lysine.sup.8 -vasopressin (LVP), oxytocin (OXY), and DDAVP are: ##STR2##
A series of vasopressin-oxytocin analogs were studied in two tests for effects on memory and/or learning. For the most part, active compounds were large peptides (8-12 amino acids). These studies also showed that various C-terminal di- and tripeptide fragments of vasopressin-oxytocin were effective in reversing puromycin-induced amnesia in mice. Pro-Arg-Gly-NH.sub.2, the C-terminal fragment of AVP, has also been reported to be active in the rat pole-climbing avoidance test.
These studies indicate that the entire sequence of amino acids in vasopressin is not an essential requirement for memory and/or learning activity. Therefore, target memory and/or learning compounds could be modeled after the C-terminal tripeptides of vasopressin-oxytocin.
Peptides consist of chains formed by amino acids linked to each other by amide bonds. ##STR3##
The amides, the side chains (R, R.sup.1) and their stereochemical attachment control the overall conformation of the peptide that results in its biological activity.
Major disadvantages of peptides as drugs have been lack of oral activity and short duration of action.
The amide bonds are responsible for the primary metabolic instability of peptides. A few reports have appeared which describe the isosteric replacement of a single amide bond in a biologically important peptide. These isosteric analogs reportedly are more potent and possess greater metabolic stability than the parent peptide. However, the other amide bonds in the peptide are susceptible to enzymatic degradation. Analogs in which all of the amide bonds have been replaced by an isosteric group have not been reported to date. Such analogs should be resistant to proteolysis and possess greater oral activity. In addition, they also should have greater lipid solubility which would lead to higher concentrations in the central nervous system.
Prolyl-leucyl-glycine (PRO-LEU-GLY) analogs have been described at the Eighth American Peptide Symposium, May 22-27, 1983 in Tucson, Ariz. T. C. Case, et al., described PRO-D-LEU-GLY-NH.sub.2 and PRO-D-LEU-GLY-NHEt as being potentially useful in treating neurological patients with movement disorders as an adjunctive drug associated with long-term administration of levodopa or other similar drugs used in treating parkinsonism.
D. Tourwe, et al., has disclosed, at the same symposium, Pro-Leu-Gly-NH.sub.2 analogs in which the Leu-Gly peptide bond has been replaced by either CH.sub.2 NH, CH.dbd.CH or C.tbd.C bonds. These compounds as MIF (melanocyte inhibitory factor) analogs are potential antidepressants.